By Robert Krochmal, MD, and Mary L. Hardy, MD
Breast and prostate malignancies are among the leading causes of cancer death in men and women in the United States.1,2 Despite advances in early detection and better initial treatments, each of these cancers still accounts for more than 200,000 newly diagnosed cases and up to 50,000 deaths per year. Given the reality of such numbers, it is imperative to develop prophylactic therapies with the potential to decrease cancer incidence. For cancers of the breast and prostate, which generally have a long latency period, there is ample opportunity to intercede preventively. In addition, patients who have survived an initial episode of cancer are very likely to be interested in dietary and lifestyle strategies to minimize risk of recurrence. For all of these reasons, there is a mandate to identify safe and effective therapies that may decrease the primary or secondary risk of cancer.
A chemopreventive agent is characterized by the ability to prevent or restrain the development of cancer. Since carcinogenesis is an extended process that can take up to 20-40 years to manifest as overt cancer, chemopreventive substances would necessarily need to be taken regularly over a long period of time. Therefore, it is essential that any agent being considered for chemoprevention have a high margin of safety and tolerability. Because a relatively low percentage of patients taking such a product would develop cancer without it, the incidence of toxic or adverse side effects must be small.
Green tea represents an ideal candidate for cancer chemoprevention. Derived from the evergreen Camellia sinensis, green tea is the most common chemopreventive drink in the world, popular for more than 4,000 years, and second only to water in worldwide consumption. It is safe, highly tolerable, and readily available in many forms, most commonly as a dried leaf for infusion. Epidemiological studies suggest a strong, dose-dependent preventive value of green tea consumption against development and recurrence of many forms of cancer, including cancers of the colon,3 prostate,4 ovary,5 and breast.6-8
Constituents and Chemistry
Green tea is grown for commercial use in more than 30 countries, and its harvest still depends on manual techniques, given that the most palatable tea comes from the young, uppermost leaves of the plant. Original tea users in China exposed the leaves to hot steam immediately after harvesting, a process that is now known to inactivate polyphenol oxidase contained in the leaves, thus preventing the breakdown of catechins.9 When the leaves are not steamed, the oxidative enzymes convert the catechins to other polyphenols, such as theaflavine gallate and thearubigins.10 This process of oxidation and subsequent fermentation leads to black tea. Oolong is a type of tea that typically has been steamed about one hour after harvesting, creating an intermediate between green and black tea.
The major polyphenols found in green tea are epicatechin, epicatechin-3-gallate, epigallocatechin, and epigallocatechin-3-gallate (EGCG) (see Figure 1). It has been estimated that up to 30% of the dry leaf weight of green tea consists of polyphenols.10 Other constituents include caffeine (1%-4%) and related methylxanthines, fiber, sugars (5%), protein (15-20%), and various micronutrients. All of these constituents have been shown to vary significantly with different commercial samples of green tea.11,12 In addition, levels of EGCG and other catechins vary according to age of the leaf and method of processing in the following order: green tea (old leaves) > green tea (young leaves) > oolong tea > black tea.13
Bioavailability
A number of Phase I trials have documented the absorption of flavonoids, leading to enhanced blood antioxidant potential.14 Upon ingestion, two kinds of transformations can occur that affect flavonoid bioavailability. First, large complex molecules may be broken down by stomach acid and digestive enzymes into smaller phenolic acids that are absorbed more easily. Then, compounds can be either absorbed and modified by the liver or further degraded by gut microflora. Therefore, the bioavailability and pharmacokinetics of green tea polyphenols represent a complex process, and their activity results not only from the parent molecules, but also from their metabolites.
Mechanism of Action
Consistent with other botanicals, green tea is distinguished by its diversity of composition compared with pharmaceutical agents that act upon a single target. Not surprisingly, studies with green tea in recent years have demonstrated an assortment of mechanisms against tumorigenesis. This multidimensionality makes green tea unique as a chemopreventive agent, since it has the ability to act upon multiple stages of cancer progression. It takes many years from the initial insult leading to malignant transformation until the ultimate progression to metastasis. As shown in Figure 2, various steps are necessary for this to occur, and there is evidence to support the role of green tea in the suppression of each of them.
Through its antioxidant capacity,12,15,16 green tea can block the initiation of malignancy by neutralizing reactive oxygen and nitrogen species that promote mutagenicity and genotoxicity. Green tea’s capacity for this action is apparent in the images of the major catechins in Figure 1, with multiple hydroxyl moieties poised to scavenge. It has been shown that the catechin content of green tea correlates with its antioxidant capacity.12 Indirectly, green tea also may exhibit antioxidant effects through inhibition of pro-oxidant enzymes, such as cyclooxygenase and nitric oxide synthase.17
A study in IL-2 deficient mice given green tea polyphenols found a decrease in interferon-gamma and tumor necrosis factor-alpha, which corresponded with lower colitis scores for the treated mice compared with placebo.18 This anti-inflammatory potential also may contribute to an ability to reduce tumorigenesis.
Another biological effect of green tea is its ability to induce apoptosis (programmed cell death) and cell cycle arrest in cancer cells.19 Apoptosis is involved in maintaining mammary epithelial cell homeostasis, thereby inhibiting the initiation, progression, and metastasis of breast cancer.20 Green tea-induced apoptosis has been found to affect the breast cancer cell lines MCF-7 and MDA-MB-231, but not normal breast epithelial cells.21 Telomerase, a factor which is elevated in more than 90% of breast cancers, has been found to be down-regulated by EGCG, leading to induction of apoptosis in MCF-7 cells, with no adverse effect on normal mammary cells.22 In prostate cancer, both androgen-sensitive and androgen-insensitive cells appear to be susceptible to EGCG-induced apoptosis.4,23
Angiogenesis (the process leading to the formation of new blood vessels) also has been proposed as a factor in tumor development and proliferation.20 Green tea extract has been shown to reduce vessel density and tumor size in breast cancer xenographs,24 which appears to be mediated through an inhibition of vascular endothelial growth factor (VEGF).25 Inhibition of VEGF also has been found in prostate cancer cells.23 Components of green tea not only decrease VEGF-promoter activity, but also epidermal growth factor receptor (EGFR)-signaling pathways.26
Various other cell-signaling pathways are affected by the constituents in green tea. For example, green tea polyphenols have been found to inhibit Her-2/neu signaling,27 a factor in breast cancer cell proliferation. In addition, EGCG appears to synergize with growth factor-dependent signals to induce p21 and impair cell cycle progression.28 A study in rats found green tea extract to decrease mammary tumor burden, potentially through induction of p27 (kip1) cyclin-dependent kinase (CKI) inhibitor expression.29 Green tea’s effects on ornithine decarboxylase also appear to play a role in decreased cellular proliferation,30 particularly in the prostate, which has the highest concentration of this enzyme.
In addition to its antioxidant, anti-inflammatory, antiangiogenesis, and antiproliferative activities, green tea may also be useful in the inhibition of metastasis through its anti-invasive actions. EGCG has been shown to be a natural inhibitor of metallo and serine proteases.31 In TRAMP mice, a model for prostate prevention, green tea at a dose equivalent to six cups per day was able to significantly inhibit metastasis to lymph nodes, liver, lung, and bone.32 Strikingly, distant metastases were reduced by fourfold compared with mice on placebo. Green tea polyphenols thus appear to suppress factors required for tumor invasion and metastasis.
Clinical Studies
Breast Cancer. Although there have been no direct clinical trials to date, epidemiologic studies have found the relative risk of breast cancer in women who are consistent tea drinkers to be as low as half that of women drinking less than one cup per month.6 A follow-up to one study found that women with a low-activity allele for catechol-O-methyltransferase (COMT), an enzyme that rapidly methylates tea polyphenols, had the highest risk reduction for breast cancer.33 This suggests that tea catechins are an active chemopreventive constituent of green tea, and that women less efficient in eliminating these compounds derive the most benefit from their consumption.
A study of breast cancer recurrence found that risk was decreased significantly among women drinking three or more cups of green tea per day.7 The highest risk reduction was found in women with earlier stages of cancer at time of initial diagnosis.
Previous studies by Fujiki et al have found that a history of consuming more than 10 cups of green tea per day led to delayed cancer onset, and that high consumption of green tea is associated with decreased axillary lymph node metastases among premenopausal women.34 Fujiki also found that stage I and II breast cancer patients consuming more than five cups per day experienced a lower recurrence rate and longer disease-free period than those consuming fewer than four cups per day.35 This led Fujiki to propose a two-stage approach to the analysis of green tea cancer prevention, namely prevention prior to cancer development and prevention following cancer diagnosis and treatment. It is possible not only that green tea can prevent the onset of cancer, but also that it can protect against recurrence, especially in the early stages.
The broad ability for green tea to be effective at both primary and secondary prevention, while exhibiting extremely low toxicity, is remarkable. Future studies should evaluate both of these potential mechanisms.
Prostate Cancer. For prostate cancer, risk appears to decrease with increasing frequency, duration, and quantity of green tea consumption. One study found a relative risk for the development of prostate malignancy to be 0.27 for those men drinking more than three cups daily.4 This risk dropped as low as 0.12 for those drinking tea for more than 40 years, and was 0.09 for those consuming more than 1.5 kg of green tea leaf per year.
As stated previously, a number of Phase I trials have documented the absorption of flavonoids leading to enhanced blood antioxidant potential,14 suggesting that orally consumed green tea components are indeed bioavailable. Henning et al recently demonstrated that green tea polyphenols were detectable in prostate tissue of men who consumed five cups daily prior to radical prostatectomy.36 It was further shown that LNCaP prostate cell proliferation was decreased when grown in a medium containing patient serum collected after green tea consumption, as compared with serum collected prior to consumption.
A Phase II trial conducted by the North Central Cancer Treatment Group at the Mayo Clinic among patients with androgen-independent prostate cancer found that green tea consumption was able to significantly decrease PSA values, while the placebo group sustained a PSA increase of 43%.37
Safety
Historical use of green tea demonstrates exceptional safety of the hot water infusion,9 and clinical trials have shown no adverse effects with concentrated, decaffeinated formulas of green tea extract equivalent to 8-16 cups per day.34,38 Most reported toxicity has been due either to temperature of the green tea taken as an infusion (increased incidence of esophageal cancer in China) or to its caffeine content (tachycardia, irritability, insomnia). Both problems are eliminated with standardized, decaffeinated capsules.
The only herb-drug interaction reported in the literature with green tea is a single case study regarding its potential inhibitory effect on warfarin.39 Warfarin produces its effect by inhibiting the production of vitamin K, and green tea may contain significant amounts of vitamin K. It is therefore advisable that any patient requiring warfarin therapy undergo close monitoring and be questioned routinely about their intake of vitamin K-containing products.
Dosage and Administration
Green tea most commonly is encountered as a dried leaf used to prepare an infusion. An average cup of green tea contains between 50 mg and 150 mg of polyphenols, depending on the amount of leaves used and the length of time they are steeped. Most of these polyphenols become available in the hot water infusion within minutes of preparation. A general rule of thumb is that 1 g of soluble components will yield about 100 mg of polyphenols in the infusion.
For those who prefer not to drink tea, given the large amount of green tea needed to demonstrate most epidemiological effects, green tea extracts have been developed for convenience and phytochemical control. Decaffeinated products prioritize the polyphenol fraction, and concentrate this component to between 60% and 89% of the weight of the extract. Three cups of green tea per day or 400 mg of standardized extract (80% total polyphenols) would supply approximately 300 mg of polyphenols. This generally is the minimum dosage that has been studied in epidemiological trials, and higher dosages appear to be well tolerated.
Conclusion
Epidemiological data suggest a clear benefit in cancer chemoprevention with green tea taken as a beverage. Although amounts of green tea consumption are not consistent among epidemiological studies, as little as 2-3 cups/d appears to be effective in some cases. Prospective, randomized, double-blind trials with green tea could provide more definitive insight into the potential of this agent against breast and prostate malignancies. Such trials will necessarily be time-consuming (generally they have a duration of five years or more); however, given the wealth of background data, they are warranted.
In any such trial, to standardize the intervention and ensure an adequate dose, utilization of a well-characterized, standardized supplement would be advisable. Furthermore, elimination of the caffeine component would not only minimize potential side effects (thus allowing higher doses), but also would strengthen the role of the polyphenol fraction of green tea as the active principle, should those studies be positive. Further studies might determine whether green tea may be used along with or as an adjuvant to chemotherapy, or whether it can be combined with other chemopreventive compounds. There is ample evidence that green tea is safe and non-toxic for most patients.
Recommendation
Given the growing data supporting the antitumor properties of green tea, the use of this botanical in the treatment and prevention of breast and prostate cancer should be strongly considered, especially as a beverage. Incorporating this drink into a daily routine is a sensible option, given its reasonable cost, palatability, and rich composition of antioxidants. The dried leaf is widely available in both loose leaf and convenient tea bag form, and the infusion is becoming more and more popular at coffee and tea shops as an alternative to coffee. For those wishing to avoid caffeine, decaffeinated forms are available.
Given that many studies show dose-dependent preventive effects, supplementation with a standardized, concentrated product is recommended for those wishing to secure a more powerful breast or prostate cancer chemopreventive regimen. This option would likely be the most beneficial for those with an environmental or familial predisposition for either disease. Since green tea is safe, readily available, effective, and relatively inexpensive, it should be considered one of the top dietary choices for patients concerned about breast or prostate cancer prevention.
Dr. Krochmal is a Fellow and Dr. Hardy is Associate Director, UCLA Center for Dietary Supplement Research: Botanicals; Dr. Hardy also is Medical Director, Cedars-Sinai Integrative Medicine Program, Los Angeles, CA.
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